Ventilator-associated events in adults: A secondary analysis assessing the impact of monitoring ventilator settings on outcomes.

BACKGROUND: Ventilator-associated events (VAE) is a tier implemented for surveillance by the CDC in the USA. Implementation usefulness for clinical decisions is unknown. METHODS: We conducted a secondary analysis from a prospective, multicentre, international study, to assess the impact on outcomes of using tiers with shorter follow-up (VAE24), lower oxygenation requirements (light-VAE) or both (light VAE24). RESULTS: A cohort of 261 adults with 2706 ventilator-days were included. The median (IQR) duration of mechanical ventilation (MV) was 9 days (5-21), and the median (IQR) length of stay in the intensive care unit (ICU) was 14 days (8-26). A VAE tier was associated with a trend to increase from 32% to 44% in the ICU mortality rates. VAE Incidence was 24 per 1,000 ventilator-days, being increased when reduced the oxygenation settings requirement (35 per 1,000 ventilator-days), follow-up (41 per 1,000 ventilator-days) or both (55 per 1,000 ventilator-days). A VAE tier was associated with 13 extra (21 vs. 8) days of ventilation, 11 (23 vs. 12) ICU days and 7 (31 vs. 14) hospitalization days, outperforming the modified tiers' performance. CONCLUSIONS: The modification of ventilator settings (consistent with ventilator-associated events) was associated with worse outcomes among adults with prolonged mechanical ventilation. Monitoring ventilator-associated events at the bedside represents a new tool for quality improvement.

Prevention of ventilator-associated pneumonia through care bundles: A systematic review and meta-analysis.

Background: Ventilator-associated pneumonia (VAP) represents a common hospital-acquired infection among mechanically ventilated patients. We summarized evidence concerning ventilator care bundles to prevent VAP. Methods: A systematic review and meta-analysis were performed. Randomized controlled trials and controlled observational studies of adults undergoing mechanical ventilation (MV) for at least 48 h were considered for inclusion. Outcomes of interest were the number of VAP episodes, duration of MV, hospital and intensive care unit (ICU) length of stay, and mortality. A systematic search was conducted in the MEDLINE, the Cochrane Library, and the Web of Science between 1985 and 2022. Results are reported as odds ratio (OR) or mean difference (MD) with 95% confidence intervals (CI). The PROSPERO registration number is CRD42022341780. Results: Thirty-six studies including 116,873 MV participants met the inclusion criteria. A total of 84,031 participants underwent care bundles for VAP prevention. The most reported component of the ventilator bundle was head-of-bed elevation (n=83,146), followed by oral care (n=80,787). A reduction in the number of VAP episodes was observed among those receiving ventilator care bundles, compared with the non-care bundle group (OR=0.42, 95% CI: 0.33, 0.54). Additionally, the implementation of care bundles decreased the duration of MV (MD=-0.59, 95% CI: -1.03, -0.15) and hospital length of stay (MD=-1.24, 95% CI: -2.30, -0.18) in studies where educational activities were part of the bundle. Data regarding mortality were inconclusive. Conclusions: The implementation of ventilator care bundles reduced the number of VAP episodes and the duration of MV in adult ICUs. Their application in combination with educational activities seemed to improve clinical outcomes.

Ventilator-associated events: From surveillance to optimizing management.

Mechanical ventilation (MV) is a life-support therapy that may predispose to morbid and lethal complications, with ventilator-associated pneumonia (VAP) being the most prevalent. In 2013, the Center for Disease Control (CDC) defined criteria for ventilator-associated events (VAE). Ten years later, a growing number of studies assessing or validating its clinical applicability and the potential benefits of its inclusion have been published. Surveillance with VAE criteria is retrospective and the focus is often on a subset of patients with higher than lower severity. To date, it is estimated that around 30% of ventilated patients in the intensive care unit (ICU) develop VAE. While surveillance enhances the detection of infectious and non-infectious MV-related complications that are severe enough to impact the patient's outcomes, there are still many gaps in its classification and management. In this review, we provide an update by discussing VAE etiologies, epidemiology, and classification. Preventive strategies on optimizing ventilation, sedative and neuromuscular blockade therapy, and restrictive fluid management are warranted. An ideal VAE bundle is likely to minimize the period of intubation. We believe that it is time to progress from just surveillance to clinical care. Therefore, with this review, we have aimed to provide a roadmap for future research on the subject.

PET Imaging of Neutrophil Elastase with 11C-GW457427 in Acute Respiratory Distress Syndrome in Pigs.

Today, there is a lack of clinically available imaging techniques to detect and quantify specific immune cell populations. Neutrophils are one of the first immune cells at the site of inflammation, and they secrete the serine protease neutrophil elastase (NE), which is crucial in the fight against pathogens. However, the prolonged lifespan of neutrophils increases the risk that patients will develop severe complications, such as acute respiratory distress syndrome (ARDS). Here, we evaluated the novel radiolabeled NE inhibitor 11C-GW457427 in a pig model of ARDS, for detection and quantification of neutrophil activity in the lungs. Methods: ARDS was induced by intravenous administration of oleic acid to 5 farm pigs, and 4 were considered healthy controls. The severity of ARDS was monitored by clinical parameters of lung function and plasma biomarkers. Each pig was studied with 11C-GW457427 and PET/CT, before and after pretreatment with the NE inhibitor GW311616 to determine in vivo binding specificity. PET image data were analyzed as SUVs and correlated with immunohistochemical staining for NE in biopsies. Results: The binding of 11C-GW457427 was increased in pig lungs with induced ARDS (median SUVmean, 1.91; interquartile range [IQR], 1.67-2.55) compared with healthy control pigs (P < 0.05 and P = 0.03, respectively; median SUVmean, 1.04; IQR, 0.66-1.47). The binding was especially strong in lung regions with high levels of NE and ongoing inflammation, as verified by immunohistochemistry. The binding was successfully blocked by pretreatment of an NE inhibitor drug, which demonstrated the in vivo specificity of 11C-GW457427 (P < 0.05 and P = 0.04, respectively; median SUVmean, 0.60; IQR, 0.58-0.77). The binding in neutrophil-rich tissues such as bone marrow (P < 0.05 and P = 0.04, respectively; baseline median SUVmean, 5.01; IQR, 4.48-5.49; block median SUVmean, 1.57; IQR, 0.95-1.85) and spleen (median SUVmean, 2.14; IQR, 1.19-2.36) was also high in all pigs. Conclusion: 11C-GW457427 binds to NE in a porcine model of oleic acid-induced lung inflammation in vivo, with a specific increase in regional lung, bone marrow, and spleen SUV. 11C-GW457427 is a promising tool for localizing, tracking, and quantifying neutrophil-facilitated inflammation in clinical diagnostics and drug development.

Dataset of coral reefs monitoring, Puerto Morelos, Mexico, 2019.

Noticeable within the Mexican Caribbean is the Arrecife de Puerto Morelos National Park (APMNP), a marine protected area established as an essential component for managing and protecting coral reefs. In June 2019, we conducted a survey in eight shallow reef sites of the APMNP with the purpose of applying a coral reef assessment method, based on biological indicators of the condition of both benthos and fish communities. In this paper we present tables with data of biological and ecological variables such as: benthos coverage, species composition and abundance of corals, abundance of urchins and coral recruits, bleaching, coral diseases and coral mortality percent, reef relief, and composition and abundance of key commercial and herbivorous fish species. The research article related to these databases was published in the journal Diversity with the title: Puerto Morelos coral reefs, current state and their classification by a scoring system.

Safety and Efficacy of Devices Delivering Inhaled Antibiotics among Adults with Non-Cystic Fibrosis Bronchiectasis: A Systematic Review and a Network Meta-Analysis.

It remains unknown whether the type of aerosol generating device is affecting efficacy and safety among non-cystic fibrosis bronchiectasis (NCFB) adults. The proposal of this network meta-analysis (NMA) is to evaluate effectiveness and safety of inhaled antibiotics administered via dry powder inhaler (DPI) and via nebulizers (SVN) among adult patients with NCFB. Inclusion criteria were randomized-controlled trials, adults (≥18 years) with NCFB, and inhaled antibiotics administered via DPI as intervention. Search strategy was performed in PubMed, Web of Science, and Cochrane Library from 2000 to 2019. Sixteen trials (2870 patients) were included. Three trials (all ciprofloxacin) used DPIs and thirteen used SVN (three ciprofloxacin). Both DPI and SVN devices achieved similar safety outcomes (adverse events, antibiotic discontinuation, severe adverse events, and bronchospasm). Administration of ciprofloxacin via DPI significantly improved time to first exacerbation (87 days, 95% CI 34.3-139.7) and quality of life (MD -7.52; 95% CI -13.06 to -1.98) when compared with via SVN. No other significant differences were documented in clinical efficacy (at least one exacerbation, FEV1% predicted) and microbiologic response (bacterial eradication, emergence of new potential pathogens, and emergence of antimicrobial resistance) when comparing devices. Our NMA documented that time to first exacerbation and quality of life, were more favorable for DPIs. Decisions on the choice of devices should incorporate these findings plus other criteria, such as simplicity, costs or maintenance requirements.

Cardiac microcalcifications in transthyretin (ATTR) amyloidosis.

BACKGROUND: Bone tracers bind to amyloid-containing heart of most patients with ATTR amyloidosis. Amyloid deposits outside the heart are often scarce and bone scintigraphy is increasingly often used to diagnose cardiac involvement. However, the nature of the binding of bone tracers to the heart is not clear. OBJECTIVE: To identify possible calcium deposits in hearts with amyloid, explaining bone tracer binding. METHODS AND RESULTS: Formalin-fixed and paraffin embedded cardiac specimens from three patients with ATTR and one with AL amyloidosis, all with cardiac deposits, were studied. The specimens covered large parts of the heart. Sections were stained immunohistochemically for ATTR deposits and according to von Kóssa for calcifications. The study identified in all hearts, but particularly in the ATTR materials, focal, tight swarms of tiny calcifications. These were sometimes associated with amyloid but found as frequent in areas without such deposits. Autoradiography with [99mTc]Tc labelled 3,3-disphos-phono-1,2-propanodicarboxylic acid (DPD) revealed labelling in von Kóssa positive areas. Electron microscopically the particles were not amorphous but had a complex structured appearance and were often surrounded by a membrane, indicating a cellular origin. Labelling with antibodies against ubiquitin and P62 pointed to result from autophagy. CONCLUSIONS: Our study indicates that binding of skeletal probes to amyloid-containing hearts depends on an irregular presence of clouds of very tiny calcifications, which seem not to be directly associated with amyloid fibrils. Therefore, [99mTc]Tc-DPD bone scans can be considered surrogate markers of ATTR amyloid but have to be used carefully to estimate amyloid amount or disease progression.

Preclinical evaluation of [11C]GW457427 as a tracer for neutrophil elastase.

INTRODUCTION: Neutrophils are part of the innate immune system and function as a first line of defense against invading microorganisms. Overactivity of the immune system may result in a devastating immuno-inflammation with extensive damage to tissue leading to organ damage and/or failure. The literature suggests several human diseases in which neutrophil elastase (NE) is postulated to be important in the pathophysiology including inflammatory bowel disease (IBD), chronic obstructive pulmonary disorder (COPD), abdominal aortic aneurysms (AAA), breast and lung cancer, and recently also in Sars-cov-2 virus infection (Covid-19). In particular, the lungs are affected by the destructive power of the protease neutrophil elastase (NE). In this paper, we report the pre-clinical development of a selective and specific positron emission tomography (PET) tracer, [11C]GW457427, as an in vivo biomarker for the study of NE, now available for human studies. METHODS: [11C]GW457427 was produced by methylation of GW447631 using [11C]methyl triflate and GMP validated production and quality control methods were developed. Chemical purity was high with no traces of the precursor GW611437 or other uv-absorbing compounds. A method for the determination of intact [11C]GW457427 in plasma was developed and the binding characteristics were evaluated in vitro and in vivo. An animal model for lung inflammation was used to investigate the specificity and sensitivity of the [11C]GW457427 tracer for neutrophil elastase (NE) in pulmonary inflammation, verified by blockade using two structurally different elastase inhibitors. RESULTS: [11C]GW457427 was obtained in approximately 45% radiochemical yield and with a radiochemical purity higher than 98%. Molar activity was in the range 130-360 GBq/µmol. Binding to NE was shown to be highly specific both in vitro and in vivo and a significantly higher uptake of tracer was found in a lipopolysaccharide mouse model of pulmonary inflammation compared with control animals. The uptake in lung tissue measured as standardized uptake value (SUV) strongly correlated with tissue NE content as measured by ELISA. In vitro studies also showed specific tracer binding in aortic tissue of patients with abdominal aorta aneurysm (AAA). The rate of metabolism in rats was appropriate considering the critical balance between available tracer for binding and requirement for blood clearance with about 40% and 20% intact [11C]GW457427 in plasma at 5 and 40 min, respectively. Radioactivity was cleared from blood and organs in control animals with mainly hepatobiliary excretion with distribution in the intestines and the urinary bladder; but without retention of the tracer in healthy organs of interests such as the lung, liver, kidneys or in the cardiovascular system. A dosimetry study in rat indicated that the whole-body effective dose was 2.2 µSv/MBq with bone marrow as the limiting organ. It is estimated that up to five PET-CT investigations could be performed in humans without exceeding a total dose of 10 mSv. CONCLUSION: [11C]GW457427 is a promising in vivo PET-biomarker for NE with high specific binding demonstrated both in vitro and in vivo. A GMP validated production method including quality control has been developed and a microdosing toxicity study performed with no adverse signs. [11C]GW457427 is currently being evaluated in a First-In-Man PET study.

Critical appraisal of international adult bronchiectasis guidelines using the AGREE II tool.

BACKGROUND: Guidelines aim to standardize and optimize diagnosis and management. We evaluated the quality of evidence supporting recommendations from different international adult guidelines on bronchiectasis, and classified with the GRADE system. METHODS: Quality of eligible clinical practice guidelines was assessed for six domains using the AGREE II tool, with ≥ 80% rating as excellent. RESULTS: Seven guidelines (283 recommendations) were analyzed, and four of them were considered "recommended for use" (three reported after 2017 as excellent). Overall, 144 (50.9%) recommendations were based on low-quality evidence, representing 81.5% in diagnosis and 36.2% in therapy. In contrast, 5/92 (5.4%) and 40/191 (20.9%) recommendations regarding diagnostic and treatment (respectively) were based on high-quality evidence. Quality agreement ratings were significantly (p< 0.05) higher for guidelines delivered after 2015, progressing from 27.7% to 58.3%, qualifying as excellent. Highest scores were documented in the domains of "scope and purpose" followed by "clarifying of presentation" and "editorial independence". CONCLUSION: Updated guidelines reported after 2017 improved quality, although well-designed randomized clinical trials remain an unmet need. AGREE II quality assessment identified four guidelines qualified as recommended for use. Improvements are required in stakeholder involvement and applicability.

Imaging of the Glucose-Dependent Insulinotropic Polypeptide Receptor Using a Novel Radiolabeled Peptide Rationally Designed Based on Endogenous GIP and Synthetic Exendin-4 Sequences.

Imaging and radiotherapy targeting the glucose-dependent insulinotropic polypeptide receptor (GIPR) could potentially benefit the management of neuroendocrine neoplasms (NENs), complementing clinically established radiopharmaceuticals. The aim of this study was to evaluate a GIPR-targeting positron emission tomography (PET) radioligand with receptor-specific binding, fast blood clearance, and low liver background uptake. The peptide DOTA-bioconjugate, C803-GIP, was developed based on the sequence of the endogenous GIP(1-30) and synthetic exendin-4 peptides with selective amino acid mutations to combine their specificity for the GIPR and in vivo stability, respectively. The 68Ga-labeled bioconjugate was evaluated in vitro in terms of binding affinity, specificity, and internalization in HEK293 cells transfected with the human GIPR, GLP1, or GCG receptors and in sections of human insulinoma and NENs. In vivo binding specificity, biodistribution, and tissue background were investigated in mice bearing huGIPR-HEK293 xenografts and in a pig. Ex vivo organ distribution, pharmacokinetics, and dosimetry were studied in normal rats. [68Ga]Ga-C803-GIP was stable and demonstrated a high affinity to the huGIPR-HEK293 cells. Binding specificity was demonstrated in vitro in frozen sections of NENs and huGIPR-HEK293 cells. No specific uptake was observed in the negative controls of huGLP1R and huGCGR cells. A novel rationally designed PET radioligand, [68Ga]Ga-C803-GIP, demonstrated promising binding characteristics and specificity towards the GIPR.

Cocoa Nanoparticles to Improve the Physicochemical and Functional Properties of Whey Protein-Based Films to Extend the Shelf Life of Muffins.

A novel nanocomposite whey protein-based film with nanoemulsified cocoa liquor (CL) was prepared using one-stage microfluidization to evaluate the emulsion properties and the effect of CL on the film properties by response surface methodology (RSM). The results indicated that the number of cycles by microfluidization had a significant effect (p < 0.05) on the particle size and polydispersity of the nanoemulsion, with a polyphenol retention of approximately 83%. CL decreased the solubility (<21.87%) and water vapor permeability (WVP) (<1.57 g mm h-1 m-2 kPa-1) of the film. FTIR analysis indicated that CL modified the secondary protein structure of the whey protein and decreased the mechanical properties of the film. These results demonstrate that applying the film as a coating is feasible and effective to improve the shelf life of bakery products with a high moisture content. This nanocomposite film is easy to produce and has potential applications in the food industry.

The sum of kidney donor profile index and estimated post-transplant survival scale and their correlation with egfr decline in deceased donor kidney recipients

Background: The impact of donor quality on post-kidney transplant survival may vary by candidate condition. Objective: Analyzing the combined use of the Kidney Donor Profile Index (KDPI) and the estimated post-transplant survival (EPTS) scale and their correlation with the estimated glomerular filtration rate (eGFR) decline in deceased-donor kidney recipients (DDKR). Methods: This was a retrospective, observational cohort study. We included DDKRs between 2015 and 2017 at a national third-level hospital. Results: We analyzed 68 DDKR. The mean age at transplant was 41 ± 14 years, 47 (69%) had sensitization events, 18 (26%) had delayed graft function, and 16 (23%) acute rejection. The graft survival at 12 and 36 months was 98.1% (95% CI 94-100) and 83.7% (95% CI 65-100), respectively. The Pearson correlation coefficient between the percentage reduction in the annual eGFR and the sum of EPTS and KDPI scales was r = 0.61, p < 0.001. The correlation coefficient between the percentage reduction in the annual eGFR and the EPTS and KDPI scales separately was r = 0.55, p < 0.001, and r = 0.53, p < 0.001, respectively. Conclusions: The sum of EPTS and KDPI scales can provide a better donor-recipient relationship and has a moderately positive correlation with the decrease in eGFR in DDKR.

PET Imaging of GPR44 by Antagonist [11C]MK-7246 in Pigs.

A validated imaging marker for beta-cell mass would improve understanding of diabetes etiology and enable new strategies in therapy development. We previously identified the membrane-spanning protein GPR44 as highly expressed and specific to the beta cells of the pancreas. The selective GPR44 antagonist MK-7246 was radiolabeled with carbon-11 and the resulting positron-emission tomography (PET) tracer [11C]MK-7246 was evaluated in a pig model and in vitro cell lines. The [11C]MK-7246 compound demonstrated mainly hepatobiliary excretion with a clearly defined pancreas, no spillover from adjacent tissues, and pancreatic binding similar in magnitude to the previously evaluated GPR44 radioligand [11C]AZ12204657. The binding could be blocked by preadministration of nonradioactive MK-7246, indicating a receptor-binding mechanism. [11C]MK-7246 showed strong potential as a PET ligand candidate for visualization of beta-cell mass (BCM) and clinical translation of this methodology is ongoing.

Para-chloro-2-[18F]fluoroethyl-etomidate: A promising new PET radiotracer for adrenocortical imaging.

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.

The Sum of Kidney Donor Profile Index and Estimated Post-Transplant Survival Scale and Their Correlation with eGFR Decline in Deceased Donor Kidney Recipients.

BACKGROUND: The impact of donor quality on post-kidney transplant survival may vary by candidate condition. OBJECTIVE: Analyzing the combined use of the Kidney Donor Profile Index (KDPI) and the estimated post-transplant survival (EPTS) scale and their correlation with the estimated glomerular filtration rate (eGFR) decline in deceased-donor kidney recipients (DDKR). METHODS: This was a retrospective, observational cohort study. We included DDKRs between 2015 and 2017 at a national third-level hospital. RESULTS: We analyzed 68 DDKR. The mean age at transplant was 41 ± 14 years, 47 (69%) had sensitization events, 18 (26%) had delayed graft function, and 16 (23%) acute rejection. The graft survival at 12 and 36 months was 98.1% (95% CI 94-100) and 83.7% (95% CI 65-100), respectively. The Pearson correlation coefficient between the percentage reduction in the annual eGFR and the sum of EPTS and KDPI scales was r = 0.61, p < 0.001. The correlation coefficient between the percentage reduction in the annual eGFR and the EPTS and KDPI scales separately was r = 0.55, p < 0.001, and r = 0.53, p < 0.001, respectively. CONCLUSIONS: The sum of EPTS and KDPI scales can provide a better donor-recipient relationship and has a moderately positive correlation with the decrease in eGFR in DDKR.

Short-Acting Sedative-Analgesic Drugs Protect Against Development of Ventilator-Associated Events in Children: Secondary Analysis of the EUVAE Study.

BACKGROUND: The U.S. Centers for Disease Control and Prevention proposed a shift in its surveillance paradigm from ventilator-associated pneumonia to ventilator-associated events (VAE) to broaden the focus of prevention and achieve a greater impact on outcomes. The main objective of the present study was to identify factors associated with pediatric VAEs in children undergoing mechanical ventilation ≥ 48 h. METHODS: This was a secondary analysis of a pediatric cohort of a multicenter prospective study. Children who underwent mechanical ventilation ≥ 48 h were included. Exclusion criteria were previous ventilation, extracorporeal life support, and right-to-left shunt or pulmonary hypertension. In the subjects with multiple episodes of mechanical ventilation, only the first episode was considered. Remifentanil and propofol are classified as short-acting sedative and analgesic agents. Pediatric VAE is defined as an "increase in PEEP ≥ 2 cm of H2O, an increase in [Formula: see text] of 0.20, or an increase in [Formula: see text] of 0.15 plus an increase in PEEP ≥ 1 cm of H2O sustained for ≥1 d. Associations with pediatric VAE were estimated through multivariate Cox proportional hazards analysis. Hazard ratios and 95% CI were computed. RESULTS: In a cohort of 90 children, 24 pediatric VAEs were documented in 906 ventilator-days. Pediatric VAEs developed after a median of 4.5 (interquartile range, 4-7.25) d. Surgical admissions, spontaneous breathing trials, early mobility, vasopressors, red blood cell units transfusion, type of sedation (continuous vs intermittent), benzodiazepine use for >3 d, and pharmacologic paralysis were not associated with pediatric VAE, whereas the use of continuous short-acting sedative-analgesic agents was identified as a strong protective factor against pediatric VAE (hazard ratio 0.06 [95% CI 0.007-0.5]). CONCLUSIONS: Treatment with short-acting sedative-analgesic agents should be preferred for sedation of mechanically ventilated children in intensive care.

Managing adult patients with infectious diseases in emergency departments: international ID-IRI study.

We aimed to explore factors for optimizing antimicrobial treatment in emergency departments. A single-day point prevalence survey was conducted on January 18, 2020, in 53 referral/tertiary hospitals in 22 countries. 1957 (17%) of 11557 patients presenting to EDs had infections. The mean qSOFA score was 0.37 ± 0.74. Sepsis (qSOFA ≥ 2) was recorded in 218 (11.1%) patients. The mean qSOFA score was significantly higher in low-middle (1.48 ± 0.963) compared to upper-middle (0.17 ± 0.482) and high-income (0.36 ± 0.714) countries (P < 0.001). Eight (3.7%) patients with sepsis were treated as outpatients. The most common diagnoses were upper-respiratory (n = 877, 43.3%), lower-respiratory (n = 316, 16.1%), and lower-urinary (n = 201, 10.3%) infections. 1085 (55.4%) patients received antibiotics. The most-commonly used antibiotics were beta-lactam (BL) and BL inhibitors (n = 307, 15.7%), third-generation cephalosporins (n = 251, 12.8%), and quinolones (n = 204, 10.5%). Irrational antibiotic use and inappropriate hospitalization decisions seemed possible. Patients were more septic in countries with limited resources. Hence, a better organizational scheme is required.

Radiolabelling and positron emission tomography imaging of a high-affinity peptide binder to collagen type 1.

INTRODUCTION: Pathological formation of fibrosis, is an important feature in many diseases. Fibrosis in liver and pancreas has been associated to metabolic disease including type 1 and 2 diabetes. The current methods for detecting and diagnosing fibrosis are either invasive, or their sensitivity to detect fibrosis in early stage is limited. Therefore, it is crucial to develop non-invasive methods to detect, stage and study the molecular processes that drive the pathology of liver fibrosis. The peptide LRELHLNNN was previously identified as a selective binder to collagen type I with an affinity of 170 nM. Radiolabelled LRELHLNNN thus constitute a potential PET tracer for fibrosis. METHOD: LRELHLNNN was conjugated to a DOTA/NOTA moiety via a PEG2-linker. DOTA-PEG2-LRELHLNNN was labelled with Gallium-68 and NOTA- PEG2-LRELHLNNN with aluminium fluoride-18. Biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was performed in healthy rats ex vivo and in vivo. The 68Ga-labelled analogue was evaluated in a mouse model of liver fibrosis by PET/MRI-imaging. The human predicted dosimetry of the tracers was extrapolated from rat ex vivo biodistribution studies at 10, 20, 40, 60, 120, 180 min (only fluoride-18) post-injection. RESULTS: The peptides were successfully radiolabelled with gallium-68 and aluminium fluoride-18, respectively. The biodistribution of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN was favorable showing rapid clearance and low background binding in organs where fibrosis may develop. Binding of [68Ga]Ga-DOTA-PEG2-LRELHLNNN to fibrotic liver was higher than surrounding tissues in mice with induced hepatic fibrosis. However, the binding was in the range of SUV 0.3, indicating limited targeting of the tracer to liver. The extrapolated human predicted dosimetric profiles of [68Ga]Ga-DOTA-PEG2-LRELHLNNN and [18F]AlF-NOTA-PEG2-LRELHLNNN were beneficial, potentially allowing at least three PET examinations annually. CONCLUSIONS: We describe the modification, radiolabelling and evaluation of the collagen type I binding peptide LRELHLNNN. The resulting radiotracer analogues demonstrated suitable biodistribution and dosimetry. [68Ga]Ga-DOTA-PEG2-LRELHLNNN exhibited binding to hepatic fibrotic lesions and is a promising tool for PET imaging of fibrosis. ADVANCES IN KNOWLEDGE: Validation of a new collagen targeting PET tracer. IMPLICATIONS FOR PATIENT CARE: Early, non-invasive diagnosis and stratification of fibrosis in order to improve the diagnosis, staging and treatment of patients with diseases involving fibrosis.